Multiple sclerosis (MS) is a demyelinating disease in the central nervous system, affecting an estimated 2.5 million people worldwide. In a typical example, demyelination occurs in a number of sites in the brain, the optic nerve, and the spinal cord in previously healthy adults in their 20 s and 30 s in the absence of particular induction, followed by development of various neurological symptoms corresponding to the foci (psychiatric disorders, palsy, visual loss, dizziness, and the like), which eventually disappear (remit) spontaneously. However, demyelination occurs again similarly (relapse) thereafter, by which patients suffer from neurological symptoms. The above-described course repeats itself many times, leaving sequelae over time, and patients become unable to walk on their own in many cases. Onset of MS itself is often unassociated with life prognoses; therefore, patients will suffer from numerous neurological sequelae for many years. Nowadays, a tendency of increase in the number of patients has been noted in Japan as well.
Causal treatment, or radical treatment, is most desired as a method of treating MS. It has been approximately 150 years since an overview of MS was proposed, during which techniques of molecular biology and the like have been developed and numerous genetic analyses have been performed. Yet, a cause of MS remains unknown and no radical treatment has been developed. A great number of pharmaceutical preparations have been developed with an aim of relapse prophylaxis and some of them have shown an effect of reducing a relapse rate to some extent; however, no treatment method to cure a disorder which has already manifested (for example, visual loss and palsy due to demyelination) has been developed yet. In view of the foregoing, development of remyelination therapy has come to be focused in Europe and the U.S., where a particularly large number of patients exist.
As noted above, MS is a disease which exhibits relapse (demyelination) and remission (spontaneous remyelination) and has such characteristics that remission becomes unable to be achieved over time and sequelae will remain (remyelination failure). Thus, it was speculated that oligodendrocytes, myelin sheath-forming cells, would disappear over time, and an attempt was made to develop neural stem cell transplant therapy for MS. On the other hand, it was reported in 1998 that a decrease in the number of oligodendrocytes was observed, while a large number of oligodendrocyte precursor cells (OPCs) remained in a demyelinating focus in MS (Non-Patent Document 1).
As of 1998, it had been elucidated that Fyn tyrosine kinase (Fyn)-mediated signal transduction was important for differentiation of OPCs (Non-Patent Document 2). It was also reported in 1999 that Fyn was essential for morphological differentiation of OPCs as well (Non-Patent Document 3). Furthermore, Nakahara et al. revealed that a γ chain of immunoglobulin Fc receptor (FcRγ) was expressed on OPCs (the expression disappeared upon completion of differentiation), and when the FcRγ on OPCs was indirectly cross-linked using IgG or the FcRγ itself was cross-linked in vitro, the expression of Fyn was increased and the strong phosphorylation of FcRγ-ITAM (Immunoreceptor Tyrosine-based Activation Motifs) by Fyn was induced, by which morphological and biochemical differentiation of OPCs was driven (Non-Patent Document 4 and Patent Document 1).
It has been pointed out that myelinolysis is involved in a number of neurological and mental diseases other than MS, such as senile dementia, Alzheimer's disease, spinal cord injury, and even diseases such as schizophrenia and manic-depressive illness; and therefore, remyelination therapy can potentially be established as a treatment method with a tremendous versatility, not only for MS.
Also, there has so far been no method to biochemically evaluate a demyelinated focus (i.e., a cluster of demyelinated nerve axons) in a living human, while indirect evaluation by MRI has been the only available option. Multiple sclerosis, which is a major demyelinating disease, is a characteristic disease exhibiting repetitive relapse and remission, and a type of disease called secondary-progressive multiple sclerosis is observed in patients with prolonged disease duration, in which clinical symptoms are slowly aggravated regardless of relapse. There are frequently cases in which it cannot necessarily be ascertained that neurological aggravation found upon consultation or self-reported aggravation in symptoms means relapse (MRI cannot necessarily visualize a relapsed lesion due to its detection limit). At present, whether or not treatment (mainly an intravenous infusion of steroid in Japan) should be given to a patient in whom aggravation as described above is suggested is up to each primary physician's discretion.    Non-Patent Document 1: Wolswijk G, J Neurosci 18:601-609, 1998    Non-Patent Document 2: Umemori H, et al. Nature 367:572-576, 1994    Non-Patent Document 3: Osterhout D J, et al., J Cell Biol 145:1209-1218, 1999    Non-Patent Document 4: Nakahara J, et al., Developmental Cell 4:841-852, 2003    Patent Document 1: International Publication WO03/011337 Pamphlet